Solid pharmaceutical dispersions with enhanced bioavailability

ABSTRACT

Spray dried solid dispersions comprising a sparingly soluble drug and hydroxypropylmethylcellulose acetate succinate (HPMCAS) provide increased aqueous solubility and/or biavailability in a use environment.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.10/458,840, filed Jun. 9, 2003, which is a Continuation of U.S. patentapplication Ser. No. 09/770,562, filed Jan. 26, 2001, which is aContinuation of U.S. patent application Ser. No. 09/131,019, filed Aug.7, 1998, now abandoned, which claims the benefit of U.S. ProvisionalPatent Application No. 60/055,221, filed Aug. 11, 1997, each of whichare hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to compositions of drugs that have increasedaqueous concentration, to processes for preparing such compositions, andto methods of using such compositions. In particular, it relates tocompositions comprising a spray dried dispersion of a sparingly solubledrug in hydroxypropylmethylcellulose acetate succinate.

BACKGROUND OF THE INVENTION

It is known in the pharmaceutical arts that low-solubility drugs oftenshow poor bioavailability or irregular absorption, the degree ofirregularity being affected by factors such as dose level, fed state ofthe patient, and form of the drug.

Solid dispersions of a drug in a matrix can be prepared by forming ahomogeneous solution or melt of the drug and matrix material followed bysolidifying the mixture by cooling or removal of solvent. Suchdispersions have been known for more than two decades. Such soliddispersions of crystalline drugs often show enhanced bioavailabilitywhen administered orally relative to oral compositions comprisingundispersed crystalline drug.

In general, it is known that the use of water-soluble polymers as thematrix material generally yields good results. Examples of water solublepolymers which have been employed include polyvinylpyrrolidone (PVP),hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC),methyl cellulose (MC), block copolymers of ethylene oxide and propyleneoxide (PEO/PPO), and polyethyleneglycol (PEG). In a 1986 review of solidamorphous dispersions, see Ford, J. L., Pharm Acta. Helv., 61:3 (1986),criteria are set forth for choosing a suitable matrix, termed a“carrier” therein. The first and most important criterion listed thereinis that the carrier “should be freely water soluble with intrinsic rapiddissolutionproperties.” As a result of this view, which is currentlywidely held, the majority of reports of solid amorphous dispersions ofdrugs in polymers use polymers which rapidly dissolve in water orgastric fluid such as PVP, PEG, or other water-soluble polymers.

There have been a relatively small number of reports of using waterinsoluble polymers as the matrix material for solid amorphousdispersions, although in some cases such polymers are soluble in aqueousbase. The clear focus of most of these reports is on achieving sustainedrelease of the drug, as opposed to increasing bioavailability. Forexample, sodium carboxymethylcellulose (NaCMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS), both polymers that are insolublein water or gastric fluid but soluble in aqueous base, such as solutionscontaining sufficient base to have a pH of 6.5 or greater followingdissolution of HPMCAS, have been used in an attempt to simultaneouslyencapsulate and form a dispersion of drug via a spray-drying process.See Wan et al., Drug Development and Industrial Pharmacy, 18:9, 997-1011(1992). The authors attempted to form a dispersion of theophylline inHPMCAS by dispersing crystals of theophylline and particles of HPMCAS inwater. Neither the drug nor the HPMCAS dissolved appreciably in thewater. The resulting slurry was spray dried and resulted in a product(p. 1009, line 11) consisting of long thin needle-like theophylline withscattered HPMCAS particles. The authors concluded (p. 1010, line 5) thatof the polymers studied, only HPMCAS was found unsuitable for theirprocess. The authors state that the intent of the process was to retardrather than enhance the rate of release of drug. Indeed, for allpolymers disclosed, in vitro tests showed drug concentrations that werethe same or lower than that obtained with drug alone.

Miyajima et al., U.S. Pat. No. 4,983,593, disclose, inter alia,formulating HPMCAS with a drug designated as NZ-105. The patentdisclosed that there is formed “a composition having a remarkablyenhanced bioavailability and easily prepared into tablets, capsules,granules, powders, and the like . . . .” The patent teaches that theformulations can be prepared by dissolving NZ-105 and HPMCAS in anorganic solvent and removing the solvent by means of vacuum-drying,spray-drying, freeze-drying, or the like, or by coating a filler such asan inorganic salt (e.g., calcium hydrogen phosphate) or a sugar (e.g.,lactose, sucrose, and so forth) and the like by means of a fluidized bedgranulation method, a centrifugal coating method, or a pan coatingmethod to produce granules. The patent discloses that granules can alsobe prepared by adding a solvent to a filler and kneading the mixturefollowed by drying. All examples in the patent describe forming adispersion of HPMCAS and NZ-105 by either (1) fluidized bed granulationby coating either calcium hydrogen phosphate particles or lactosecrystals to form large particles up to 1400 μm in diameter or 2) vacuumdrying with lactose to form a solid cake that is then pulverized to forma powdery material.

Nakamichi et al., U.S. Pat. No. 5,456,923, disclose, inter alia, aprocess for producing solid dispersions by passing a mixture of a drugand a polymer carrier through a twin screw compounding extruder. HPMCASis mentioned as one polymer from among a group of suitable polymerswhich can be used.

U.S. Pat. No. 5,456,923 to Shogo et al discloses an extrusion method formaking solid dispersions. HPMCAS is included in a list of polymericmaterials, including materials such as starch or gelatin, that can beused as matrix materials.

Takeichi et al, Chem. Pharm. Bull, 38 (9), 2547-2551 (1990) attempted touse a solid dispersion of HPMCAS and uracil made by grinding in a ballmill to enhance rectal absorption, but concluded that uracil absorptionwas lower than for low molecular weight matrix materials such as sodiumcaprate. The use of HPMCAS was not recommended.

Baba, et al, Chem. Pharm. Bull, 38 (9), 2542-2546 (1990) made groundmixtures of uracil and HPMCAS along with 50 other matrix materials.Although some enhancement (about a factor of 2) in the dissolution ofuracil was observed in the co-ground HPMCAS material relative to asimple mixture of crystalline drug and HPMCAS, the enhancement decreasedas the polymer-to-drug ratio was increased. This led the researchers toconclude that HPMCAS adsorbed on the surface of the uracil therebyhindering the dissolution of uracil. Its use was not recommended.

T. Yamaguchi et al, Yakuzaigaku, 53 (4), 221-228 (1993) prepared solidamorphous dispersions of 4″-O-(4-methoxyphenyl)acetyltylosin (MAT) inHPMCAS as well as CMEC. Dissolution tests at pH 4.0 showedsupersaturated concentrations of MAT 9-fold that of crystalline MAT withHPMCAS dispersions. This concentration was comparable to that obtainedwith the dissolution of amorphous drug alone. However, the presence ofHPMCAS sustained the supersaturation longer than the amorphous drugalone. The authors report that even better results were obtained withthe CMEC dispersions, however, causing the authors to conclude that CMECis the preferred dispersion matrix.

SUMMARY OF THE INVENTION

In a first aspect, this invention provides a composition comprising aspray dried solid dispersion, which dispersion comprises a sparinglywater-soluble drug and hydroxypropylmethylcellulose acetate succinate(HPMCAS), said dispersion providing a maximum concentration of said drugin a use environment that is higher by a factor of at least 1.5 relativeto a control composition comprising an equivalent quantity ofundispersed drug.

In another aspect, this invention provides a method of increasing thebioavailability of a sparingly-soluble drug, comprising administeringsaid drug in a composition comprising a spray dried solid dispersion,which dispersion comprises said drug and hydroxypropylmethylcelluloseacetate succinate (HPMCAS), said dispersion providing a concentration ofsaid drug in a use environment that is higher by a factor of at least1.5 relative to a composition comprising an equivalent quantity ofundispersed drug.

In another aspect this invention provides a process for making a spraydried solid dispersion comprising

A. forming a solution comprising (i) HPMCAS, (ii) a sparinglywater-soluble drug, and (iii) a solvent in which both (i) and (ii) aresoluble; and

B. spray drying said solution, thereby forming spray dried particleshaving an average diameter less than 100 μm. In a preferred embodimentthe concentration of drug in the solvent is less than 20 g/100 g ofsolvent with a total solids content less than 25 weight %, preferablyless than 15 weight %. In another preferred embodiment the spray dryingis conducted under conditions whereby the droplets solidify in less than20 seconds.

The sparingly soluble drugs suitable for use in this invention can becrystalline or amorphous in their undispersed state. A crystalline drug,once dispersed, is substantially non-crystalline as determined byscanning calorimetry or x-ray diffraction.

The term “drug” in this specification and the appended claims isconventional, denoting a compound having beneficial prophylactic and/ortherapeutic properties when administered to an animal, including humans.

A use environment can be either the in vivo environment of thegastrointestinal tract of an animal, particularly a human, or the invitro environment of a test solution, an example being “MFD” (for modelfasted duodenal) solution. A dispersion (or a composition comprising adispersion) can correspondingly be tested in vivo or, more conveniently,tested in vitro as further disclosed and discussed below to ascertainwhether it is within the scope of the invention.

In a preferred embodiment the drug/HPMCAS spray dried dispersion itselfconsists essentially of sparingly soluble drug and HPMCAS. Othercomponents can be included in the dispersion if they are inert in thesense that they do not adversely affect the maximum supersaturatedconcentration (MSSC) of drug achievable with the dispersion in a useenvironment. Components which do affect the MSSC can also be included,so long as they do not adversely affect (i.e., by lowering) the MSSCmaterially, meaning that all such components in the dispersion do notlower the MSSC by more than 20% relative to a spray dried dispersion notcontaining such components. Components which do not affect, or in factimprove MSSC, can be included in any amount. Generally, the amount ofHPMCAS and drug in the dispersion, not counting any residual solvent,should be greater than 75% by weight.

In vitro, a composition of matter comprising a spray-dried dispersion ofa sparingly soluble drug in HPMCAS is within the scope of the inventionif, when said dispersion is dissolution tested, the maximumsupersaturated concentration of said drug achievable with saiddispersion is higher by a factor of at least 1.5 relative to theequilibrium concentration achieved by dissolution testing a compositioncomprising an equivalent quantity of undispersed drug. “Dissolutiontesting” refers to a repeatable, standardized test which employs, as atest medium, an aqueous liquid in which HPMCAS is soluble. Generally,aqueous liquids (i.e., water solutions) having a pH of 6 and higherfollowing dissolution of HPMCAS are satisfactory. Of course, the testshould also be capable of reproducibly evaluating equilibrium and/orsupersaturated concentrations of a drug. A convenient dissolution testemploys MFD solution as a test medium in a USP-2 apparatus as describedin United States Pharmacopoeia XXIII (USP) Dissolution Test Chapter 711,Apparatus 2. Solution volume, paddle speed and temperature are notconsidered to be critical so long as test dispersions and controls aretested under like or standardized conditions, for example 500 mL of MFD,paddle speed of 100 rpm, and 37° C. Other values for these parameterscan be employed so long as they are maintained constant such that theconcentrations being measured are measured under the same conditions.Dissolution testing is typically conducted by comparing a testcomposition comprising a drug/HPMCAS dispersion with a controlcomposition identical except that it contains pure drug in itsequilibrium—either crystalline or amorphous-form. The controlcomposition is typically the same as the test composition but for theinclusion of HPMCAS. The HPMCAS can simply be omitted altogether andjust the drug added to the remainder of the composition, or the HPMCAScan be replaced by an equal amount of inert, non-adsorbing solid diluentsuch as microcrystalline cellulose. Thus, the control composition shouldalso contain any excipients and/or other components, in the amounts suchother components are contained by the test composition.

Preferred dispersions are those for which the in vitro (e.g., MFD) drugconcentration falls to no less than 25% of the MSSC during the 15minutes after MSSC is reached, preferably 30 minutes after MSSC isreached.

In the same manner, a composition of matter comprising a spray-drieddispersion of a sparingly soluble drug in HPMCAS is within the scope ofthe invention if, when a composition comprising said dispersion istested in vivo, the Cmaxachieved with said composition is higher by afactor of at least 1.25 (i.e., 25% higher) relative to the Cmaxachievedwith a composition comprising an equivalent quantity of undisperseddrug. As indicated above, Cmaxis an abbreviation for the maximum drugconcentration in serum or plasma of the test subject. In vivo testingprotocols can be designed in a number of ways. By measuring the Cmaxfora population to which the test composition has been administered andcomparing it with the Cmaxfor the same population to which the controlhas also been administered, the test composition can be evaluated.

Compositions according to the invention exhibit at least a factor of1.25 improvement in AUC, which is a determination of the area under acurve (AUC) plotting the serum or plasma concentration of drug along theordinate (Y-axis) against time along the abscissa (X-axis). Generally,the values for AUC represent a number of values taken from all thesubjects in a patient test population and are, therefore, mean valuesaveraged over the entire test population. By measuring the AUC for apopulation to which the test composition has been administered andcomparing it with the AUC for the same population to which the controlhas been administered, the test composition can be evaluated. AUC's arewell understood, frequently used tools in the pharmaceutical arts andhave been extensively described, for example in “PharmacokineticsProcesses and Mathematics”, Peter E. Welling, ACS Monograph 185; 1986.AUCs for this invention were typically determined over a period of 48 or72 hours starting from the time the dispersion or control was firstadministered.

Thus, a composition is within the scope of the invention if it exhibitsin vivo either a Cmax or an AUC that is 1.25 times the correspondingCmax or AUC exhibited by a composition comprising an equivalent quantityof undispersed drug. In a preferred embodiment, compositions accordingto the invention, in addition to displaying at least a factor of 1.25improvement in Cmax as discussed above, also exhibit at least a factorof 1.25 improvement in AUG,

Cmax and AUC can be determined in humans or a suitable animal model,such as dogs.

A “sparingly-soluble drug” as employed above applies to drugs which areessentially totally water-insoluble or poorly water-soluble. Morespecifically, the term applies to any beneficial therapeutic agent whichhas a dose (mg) to aqueous solubility (mg/ml) ratio greater than 100 ml,where the drug solubility is that of the neutral (e.g., free base orfree acid) form in unbuffered water. This definition includes but is notlimited to drugs that have essentially no aqueous solubility (less than1.0 μg/ml) since it has been determined that the invention has benefitfor such drugs. In general, the drug is dispersed in the HPMCAS suchthat most of the drug is not present in crystalline form greater thanabout 0.1μ in diameter. The drug may be present in amorphous drug-richdomains as long as the drug will dissolve to form supersaturatedsolutions in in vitro tests disclosed hereinafter. However, it isgenerally preferred for the drug to be molecularly dispersed such thatthere is little or no drug present as separate amorphous domains.

For the purposes of this invention, a “sparingly soluble amorphous drug”is a drug that, in its amorphous state, is sparingly soluble asdescribed above and also, upon storage for 30 days at 30° C. shows notendency to crystallize as measured by calorimetric techniques or powderx-ray diffraction. An example of such a drug isN-tert-butyl-2-{3-[3-(3-chloro-phenyl)-unreido]-8-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydrobenxo[b]azepin-1-yl}-acetamide,which has an aqueous solubility (pH 6.5) of less than 3.0 μg/ml and abroad melting range of 115° to 137° C.

A preferred class of compounds for use in this invention is glycogenphosphorylase inhibitors, such as those disclosed in PCT/IB95/00443,published internationally as WO96/39385 on Dec. 12, 1996. Specificcompounds include those having the structures

Another preferred class of compounds for use in this invention is5-lipoxygenase inhibitors, such as those disclosed in PCT/JP94/01349,published as WO 95/05360. A preferred compound has the structure

Another preferred class of compounds for use in this invention iscorticotropic releasing hormone (CRH) inhibitors such as those disclosedin PCT/IB95/00439 published as WO95/33750. Specific compounds includethose having the following structure:

Another preferred class of compounds is antipschotics. A particularlypreferred compound is ziprasidone.

Other preferred compounds include griseofulvin, nifedipine, andphenyloin.

The specific compounds and classes disclosed above are understood toinclude all forms thereof, including pharmaceutically acceptable salts,hydrates, polymorphs, and steroisomers.

“MFD” is an acronym meaning “model fasted duodenal” fluid which isemployed as an in vitro test medium for purposes of determining whethera particular drug/HPMCAS dispersion falls within the scope of thisinvention. The MFD test medium allows testing in more convenient invitro conditions and environment by virtue of mimicking an in vivoenvironment. For purposes of this invention, MFD is water which is 82 mM(millimolar) in NaCl, 20 mM in Na₂HPO₄, 47 mM in KH₂PO₄, 14.7 mM insodium taurocholate and 2.8 mM in1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine to yield a solution pHof about 6.5 and osmotic pressure of about 290 mOsm/kg. MFD is describedin greater detail below.

The term “HPMCAS” as used herein refers to a family of cellulosederivatives that can have (1) two types of ether substituents, methyland/or 2-hydroxypropyl and (2) two types of ester substituents, acetyland/or succinyl. It is referred to in scientific literature asO-(2-hydroxypropyl)-O-methyl-cellulose acetate succinate. The degree ofsubstitution for each of the four general types just noted can be variedover a wide range to effect the chemical and physical properties of thepolymer. This versatility of HPMCAS allows its structure to be optimizedto obtain good performance with a particular drug of interest. HPMCAScan be synthesized as noted below or purchased commercially. Threeexamples of commercially available HPMCAS include Shin-Etsu AQOAT®-LF,Shin-Etsu AQOAT®-MF, and Shin-Etsu AQOAT®-HF. All three of thesepolymers are manufactured by Shin-Etsu Chemical Co., Ltd. (Tokyo,Japan), and all three have proven to be suitable for use in practicingthe present invention. The specific grade that yields the bestperformance for obtaining and sustaining supersaturation in in vitrotests and obtaining high bioavailability in vivo, varies depending onthe specific chemical and physical properties of the drug to bedelivered. A preferred mean weight average molecular weight range forHPMCAS is 10,000 to one million daltons, preferably 10,000 to 400,000daltons, as determined using polyethylene oxide standards.

Drugs which are preferred for use in this invention include those whichhave a dose to aqueous solubility greater than 100, where the aqueoussolubility is measured in unbuffered water. For ionizable compounds, theappropriate solubility is that of the free base, free acid, orzwitterion, i.e., the solubility of the neutral form. Drugs which willparticularly benefit from formulation in spray-dried HPMCAS dispersionsof this invention include those drugs which have a dose to aqueoussolubility ratio greater than 500. Examples of such drugs are disclosedin the examples herein.

In general, when “solubility” is referred to, aqueous solubility isintended unless otherwise indicated.

It has been determined that a spray dried solid dispersion of asparingly-soluble drug in HPMCAS has unique properties making it broadlyuseful for preparing oral dosage forms. While not wishing to be bound byany particular theory or mechanism, it is believed that in order for asolid amorphous dispersion of a drug in a matrix material to functionoptimally in improving the bioavailability of sparingly-soluble drugs,the matrix material must generally provide the following functions:

1. disperse the drug, thereby preventing or retarding the rate ofcrystallization in the solid state,

2. dissolve in vivo, thereby allowing the drug to be released to thegastrointestinal tract,

3. inhibit the precipitation or crystallization of aqueous dissolveddrug.

It has been determined that a spray-dried solid dispersion of asparingly soluble drug in HPMCAS is superior insofar as above functions1-3 are concerned, and that such dispersions provide unexpectedly goodformulatability and solubility.

If a drug does not have a strong tendency to crystallize from theamorphous solid state, then only the latter two functions are required.When a solid amorphous dispersion of a drug in HPMCAS is prepared, thedrug will, either prior to or following dissolution of the drug HPMCASdispersion, reach a concentration substantially higher than theequilibrium solubility of the drug alone. That is, the drug reaches asupersaturated concentration, and this supersaturated concentration willbe maintained for a relatively long time period. HPMCAS functions wellin all three respects noted above such that it is unique among knownmatrix materials in its ability to inhibit the precipitation orcrystallization of a broad range of sparingly soluble drugs from asupersaturated solution. Further, and again without wishing to be boundby theory, it is believed that spray drying effects rapid solventremoval so that crystallization of drug and HPMCAS is largely prevented,or at least minimized relative to other methods of forming dispersions,including other solvent removal processes such as rotary evporation. Inaddition, in many cases spray drying effects removal of solventsufficiently fast that even phase separation of amorphous drug andHPMCAS is largely prevented or minimized. Thus, HPMCAS and spray dryingafford a better, more truly homogeneous dispersion in which the drug ismore efficiently dispersed in the polymer. Increased efficiency ofdispersion from spray drying gives, relative to other methods of makingdispersions, a higher drug concentration in in vitro tests.

Surprisingly, a solid amorphous dispersion comprising a spray driedmixture of HPMCAS and a sparingly soluble amorphous drug, that is, onethat shows little tendency to crystallize from its amorphous state canbenefit from this invention. Solid dispersions of such drugs in HPMCASsurprisingly show high degrees and durations of supersaturation in invitro dissolution tests relative to compositions comprising undispersedamorphous drug. This finding runs contrary to conventional wisdom inthat attempts to enhance the bioavailability of drugs by making solidamorphous dispersions have been directed exclusively toward drugs that,in their pure state, are crystalline or, if made amorphous,spontaneously progress toward the crystalline state. In fact, in thecourse of developing an appropriate matrix material, two in vitroscreening methods (see Examples 2 and 3) have been developed andemployed to screen a wide range of drugs. The results of these in vitroscreening tests, based on drug levels in MFD solution, are predictive ofin vivo bioavailability based on drug levels in blood when dosed orallyto dogs or humans. Results obtained from these screening tests supportthe surprising finding that amorphous dispersions of hydrophobic drugsthat are either amorphous in their pure state or show little tendency tobe crystalline (e.g., crystal forces are low) also have greatly improveddegrees and durations of supersaturation in in vitro dissolution testsrelative to amorphous drug alone. This finding is surprising in thatconventional wisdom holds that the function of dispersing a drug in amatrix material is to prevent or retard its crystallization, and thusthat using such matrices should do little to increase the solubility ofa drug which is already non-crystalline.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic diagram of a mini spray drying apparatus used forthe examples.

FIG. 2 is a schematic diagram of a micro spray drying apparatus used forthe examples.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

Synthesis of HPMCAS can be conducted by treatingO-(hydroxypropyl)-O-methylcellulose with acetic anhydride and succinicanhydride, as set forth in Tezuka et al, Carbohydrate Research222(1991)255-259 and in Onda et al, U.S. Pat. No. 4,385,078, theteachings of which are incorporated herein by reference. Although suchderivatives of cellulose are often considered in the literature assimply having varying average amounts of the four substituents attachedto the three hydroxyl groups on each of the glucose repeat units ofcellulose, ¹³C-NMR research suggests that most of the hydroxyl groupsinitially present on the 2-hydroxypropyl groups are substituted bymethyl, acetyl, succinyl, or a second 2-hydroxypropyl group, see U.S.Pat. No. 4,385,078. Although essentially any degree of substitution ofthe various groups can be used as long as the resulting polymer issoluble at the pH of the small intestine, e.g., pH 6 to 8, the amountsof the substituents methoxy, hydroxypropoxy, acetyl, and succinyl, aregenerally in the range of 10 to 35 wt %, 3 to 15 wt %, 3 to 20 wt %, and2 to 30 wt %, respectively. Preferably, the amounts of the substituentsare 15 to 30 wt %, 4 to 11 wt %, 4 to 15 wt %, and 3 to 20 wt %,respectively. Alternatively, HPMCAS may easily be purchased from anumber of commercial suppliers.

The amount of HPMCAS relative to the amount of drug present in thedispersions of the present invention can vary widely from a drug:polymerweight ratio of 1 to 0.2 to 1 to 100. However, in most cases it ispreferred that the drug to polymer ratio is greater than 1 to 0.4 andless than 1 to 20. The minimum drug:polymer ratio that yieldssatisfactory results varies from drug to drug and is best determined inthe in vitro dissolution tests described below.

Although the key ingredients present in the solid amorphous compositionsof the present invention are simply the drug to be delivered and HPMCAS,the inclusion of other excipients in the dispersion may be useful andeven preferred. For example, polymers other than HPMCAS that are solublein aqueous solutions over at least a portion of the range pH 1.0 and 8.0can be included in the dispersion along with HPMCAS. For example, it hasbeen found that amorphous dispersions of drug and conventional matrixmaterials such as PVP, HPC, or HPMC can be formed and then trituratedwith HPMCAS and still have, for some drugs, superior performancerelative to the same dispersions without HPMCAS. In such cases, itappears that, whether the drug is crystalline or amorphous, HPMCAS mayhave as its primary benefit inhibition of the precipitation orcrystallization of drug from supersaturated solution. Included as apreferred embodiment of this invention are dispersions in which drug,HPMCAS, and one or more additional polymers are co-spray dried, whereindrug and HPMCAS constitute not more than 75% of the dispersion.

Another type of excipient useful as a component of the dispersionsherein is a surface-active agent such as a fatty acid and alkylsulfonate; commercial surfactants such as those sold under tradenamessuch as benzethanium chloride (Hyamine® 1622, available from Lonza,Inc., Fairlawn, N.J., docusate sodium (available from Mallinckrodt Spec.Chem., St. Louis, Mo., and polyoxyethylene sorbitan fatty acid esters(Tween®, available from ICI Americas Inc, Wilmington, Del., Liposorb®P-20, available from Lipochem Inc, Patterson, N.J., and Capmul® POE-0,available from Abitec Corp., Janesville, Wis.), and natural surfactantssuch as sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and otherphospholipids and mono- and diglycerides. Such materials canadvantageously be employed to increase the rate of dissolution byfacilitating wetting, thereby increasing the maximum drug concentrationand the degree of supersaturation attained, and also to inhibitcrystallization or precipitation of drug by interacting with dissolveddrug by mechanisms such as complexation, formation of inclusioncomplexes, formation of micelles or adsorbing to the surface of soliddrug, crystalline or amorphous. These surface active agents may compriseup to 25% of the spray-dried dispersion.

Addition of pH modifiers such as acids, bases, or buffers can also bebeneficial. pH modifiers can advantageously serve to retard thedissolution of the dispersion (e.g., acids such as citric acid orsuccinic acid) or, alternatively, to enhance the rate of dissolution ofthe dispersion (e.g., bases such as sodium acetate or amines). Additionof conventional matrix materials, surface active agents, fillers,disintegrants, or binders may be added as part of the dispersion itself,added by granulation via wet or mechanical or other means. When suchadditives are included as part of the dispersion itself, they can bemixed with drug and HPMCAS in the spray drying solvent, and may or maynot dissolve along with the drug and HPMCAS prior to forming thedispersion by spray drying. These materials may comprise up to 25% ofthe drug/HPMCAS/additive dispersion.

In addition to drug and HPMCAS (and other polymers as discussedimmediately above), other conventional formulation excipients can beemployed in the compositions of this invention, including thoseexcipients well known in the art. Generally, excipients such as fillers,disintegrating agents, pigments, binders, lubricants, flavorants, and soforth can be used for customary purposes and in typical amounts withoutaffecting the properties of the compositions. These excipients areutilized after the HPMCAS/drug dispersion has been formed, in order toformulate the dispersion into tablets, capsules, suspensions, powdersfor suspension, creams, transdermal patches, and the like.

The term spray-drying is used conventionally and broadly refers toprocesses involving breaking up liquid mixtures into small droplets(atomization) and rapidly removing solvent from the mixture in acontainer (spray-drying apparatus) where there is a strong driving forcefor evaporation of solvent from the droplets. The strong driving forcefor solvent evaporation is generally provided by maintaining the partialpressure of solvent in the spray-drying apparatus well below the vaporpressure of the solvent at the temperature of the drying droplets. Thisis accomplished by either (1) maintaining the pressure in thespray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2)mixing the liquid droplets with a warm drying gas; or (3) both. Forexample, a solution of drug and HPMCAS in acetone can be suitablyspray-dried by spraying the solution at a temperature of 50° C. (thevapor pressure of acetone at 50° C. is about 0.8 atm) into a chamberheld at 0.01 to 0.2 atm total pressure by connecting the outlet to avacuum pump. Alternatively, the acetone solution can be sprayed into achamber where it is mixed with nitrogen or other inert gas at atemperature of 80° C. to 180° C. and a pressure of 1.0 to 1.2 atm.

Generally, the temperature and flow rate of the drying gas is chosen sothat the HPMCAS/drug-solution droplets are dry enough by the time theyreach the wall of the apparatus that they are essentially solid, so thatthey form a fine powder and do not stick to the apparatus wall. Theactual length of time to achieve this level of dryness depends on thesize of the droplets. Droplet sizes generally range from 1 μm to 500 μmin diameter, with 5 to 100 μm being more typical. The largesurface-to-volume ratio of the droplets and the large driving force forevaporation of solvent leads to actual drying times of a few seconds orless. This rapid drying is critical to the particles maintaining auniform, homogeneous composition instead of separating into drug-richand polymer-rich phases. Such dispersions which have a homogeneouscomposition can be considered solid solutions and may be supersaturatedin drug. Such homogeneous dispersions are preferred in that the MSSCvalue obtained when a large amount of drug is dosed can be higher forsuch dispersions relative to dispersions for which at least a portion ofthe drug is present as a drug-rich amorphous or crystalline phase.Solidification times should be less than 20 seconds, preferably lessthan 5 seconds, and more preferably less than 2 seconds. In general, toachieve this rapid solidification of the drug/polymer solution, it ispreferred that the size of droplets formed during the spray dryingprocess are less than 100 μm in diameter, preferably less than 50 μm indiameter, and more preferably less than 25 μm in diameter. The resultantsolid particles thus formed are generally less than 100 μm in diameter,preferably less than 50 μm in diameter, more preferably less than 25 μmin diameter.

Following solidification, the solid powder may stay in the spray-dryingchamber for 5 to 50 seconds, further evaporating solvent from the solidpowder. The final solvent content of the solid dispersion as it exitsthe dryer should be low, since this reduces the mobility of drugmolecules in the dispersion, thereby improving its stability. Generally,the residual solvent content of the dispersion should be less than 10 wt% and preferably less than 2 wt %.

The dispersions can then be post-processed to prepare them foradministration using methods known in the art such as roller compaction,fluid bed agglomeration, or spray coating.

Spray-drying processes and spray-drying equipment are describedgenerally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H.Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984, page20-54 to 20-57. More details on spray-drying processes and equipment arereviewed by Marshall (“Atomization and Spray-Drying,” Chem. Eng. Prog.Monogr. Series, 50 [1954] 2).

The solution spray-dried to form the HPMCAS/drug dispersion can containonly drug and HPMCAS in a solvent. Typically, the ratio of drug toHPMCAS in the solution ranges from 1 to 0.2 to 1 to 100 and preferablyranges from 1 to 0.4 to 1 to 20. However, when the drug dose is low(less than 20 mg), thedrug-to-HPMCAS ratio can be even higher than 20.Essentially, solvents suitable for spray-drying can be any organiccompound in which the drug and HPMCAS are mutually soluble. Preferably,the solvent is also volatile with a boiling point of 150° C. or less.Preferred solvents include alcohols such as methanol, ethanol,n-propanol, iso-propanol, and butanol; ketones such as acetone, methylethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetateand propylacetate; and various other solvents such as acetonitrile,methylene chloride, toluene, and 1,1,1-trichloroethane. Lower volatilitysolvents such as dimethyl acetamide or dimethylsulfoxide can also beused. Mixtures of solvents can also be used, as can mixtures with wateras long as the polymer and HPMCAS are sufficiently soluble to make thespray-drying process practical.

Spray-dried solutions and the resulting dispersions can also containvarious additives that aid in the stability, dissolution, tableting, orprocessing of the dispersion. As mentioned previously, examples of suchadditives include: surfactants, pH-controlling substances (e.g., acids,bases, buffers), fillers, disintegrants, or binders. Such additives canbe added directly to the spray-drying solution such that the additive isdissolved or suspended in the solution as a slurry. Alternatively, suchadditives can be added following the spray-drying process to aid informing the final dosage form.

In a further aspect this invention provides an in vitro test forevaluating the performance of HPMCAS candidate dispersion compositions,thereby allowing the identification of dispersion compositions that willyield good in vivo bioavailability of drug when taken orally. It hasbeen determined that in vitro dissolution of a dispersion inmodel-fasted duodenal (MFD) solution is a good indicator of in vivoperformance and bioavailability. In particular, a candidate dispersioncan be dissolution tested by adding it to MFD solution and agitating toassist in dissolution. In this test, the amount of dispersion is chosensuch that if all drug dissolves, a 1.5-fold or greater supersaturatedsolution is obtained. A dispersion is within the scope of this inventionif the maximum supersaturated concentration of drug exceeds, by a factorof at least 1.5, the equilibrium concentration of a control compositioncomprising an equivalent quantity of undispersed drug. As previouslydiscussed, the comparison composition is conveniently the undisperseddrug alone (e.g., pure drug in its equilibrium state—either crystallineor amorphous) or the undispersed drug plus a weight of inert diluentequivalent to the weight of HPMCAS in the test composition. Preferablythe supersaturated concentration of drug achieved with the testdispersion exceeds the equilibrium drug concentration by a factor of atleast three, and most preferably by a factor of at least five.

A typical test can be conducted by (1) dissolving a sufficient quantityof control composition, typically the candidate drug alone, to achieveequilibrium drug concentration; (2) dissolving a sufficient quantity oftest dispersion to achieve a maximum supersaturated drug concentration;and (3) determining whether the supersaturated concentration exceeds theequilibrium concentration by a factor of at least 1.5. The concentrationof dissolved drug is typically measured as a function of time bysampling the solution and plotting concentration vs. time so that theconcentration maximum can be ascertained. For purposes of avoiding drugparticulates which would give an erroneous determination in the test,the test solution is either filtered or centrifuged. “Dissolved drug” istypically taken as that material that either passes a 0.45 μm syringefilter or, alternatively, that material that remains in the supernatantfollowing centrifugation. Filtration can be conducted using a 13 mm,0.45 μm polyvinylidine difluoride syringe filter sold by ScientificResources under the trademark Titan®. Centrifugation is typicallycarried out in a polypropylene microcentrifuge tube by centrifuging at13,000 G for 60 seconds using any centrifuge suitable for the purpose.Other similar filtration or centrifugation methods can be employed anduseful results obtained. For example, using other types of microfiltersmay yield values somewhat higher or lower (plus or minus 10 to 40%) thanthat obtained with the filter specified above but will still allowidentification of suitable dispersions.

Dispersions can also be tested in dogs as follows:

Beagle dogs (typically n=4-6) that have been fasted the previous day areadministered the formulation in the fasted or fed state (fasted state:no food is allowed until after an 8 hr blood sample; fed state: a mealof 14 g of dry dog food and 8 g of olive oil (this meal imitates thehigh fat “FDA breakfast”) immediately before dosing test or controlcomposition, and regular rations after the 8 hr sample).

The test and control formulations are administered, via oral gavage inwater or 0.2% aqueous polysorbate 80 to aid in wetting, through PE205tubing attached to a syringe. Dogs are returned to metabolism cages withnormal access to water. Alternatively, dosing may be via capsules ortablets, with the provision that the test and control formulations beidentical, except for the presence or absence of HPMCAS.

Blood samples are taken from the jugular vein using a 10 ml disposablesyringe with a 20 gauge needle at 0.5, 1, 1.5, 2, 3, 4, 6, 8 (andoccasionally 12 hr) hours post dose. Other sampling times may be usedwith the conditions that T_(max) is bracketed by the sampling intervalsand that an accurate AUC may be calculated. Samples are immediatelytransferred to clean glass culture tubes containing heparin. Samples arecentrifuged at room temperature at 3000 rpms for 5 minutes. Plasma istransferred to clean glass 1 dram vials using a 5¼″ pasteur pipette.Plasma samples are frozen on dry ice and stored in a laboratory freezeruntil assayed by HPLC.

From plasma or serum drug concentrations, typical pharmacokineticparameters, such as C_(max), T_(max) and AUC are calculated for eachdog, and then averaged for the test population.

Dispersions can be tested in vivo in humans as follows. In a crossoverdesign, 4 or more healthy human subjects are dosed with a suspension ofcrystalline drug (or amorphous drug if the drug does not crystallize) ora suspension of drug/HPMCAS spray-dried dispersion. Blood samples aretaken before dosing and at a variety of times post-dosing, with thenumber and temporal distribution of sampling times chosen to bracketT_(max) and permit accurate measurement of AUC. Drug concentration inplasma or serum is measured by an appropriate assay, and C_(max),T_(max), and AUC are determined. A dispersion of this invention is aspray-dried drug/HPMCAS dispersion which, when tested in an animalspecies:

(a) exhibits a drug C_(max) which is greater than 1.25-fold the C_(max)determined after dosing crystalline drug alone (or amorphous drug if thedrug does not crystallize), or

(b) exhibits a drug AUC which is greater than 1.25-fold the AUCdetermined after dosing crystalline drug alone (or amorphous drug if thedrug does not crystallize).

Preferred drug/HPMCAS dispersions are those which satisfy both the (a)and (b) criteria above.

Compositions of this invention can be used in a wide variety of formsfor administration of drugs orally. Exemplary dosage forms are powdersor granules that can be taken orally either dry or reconstituted byaddition of water to form a paste, slurry, suspension or solution;tablets, capsules, or pills. Various additives can be mixed, ground, orgranulated with the compositions of this invention to form a materialsuitable for the above dosage forms. Potentially beneficial additivesfall generally into the following classes: other matrix materials ordiluents, surface active agents, drug complexing agents or solubilizers,fillers, disintegrants, binders, lubricants, and pH modifiers (e.g.,acids, bases, or buffers).

Examples of other matrix materials, fillers, or diluents includelactose, mannitol, xylitol, microcrystalline cellulose, calciumdiphosphate, and starch.

Examples of surface active agents include sodium lauryl sulfate andpolysorbate 80.

Examples of drug complexing agents or solubilizers include thepolyethylene glycols, caffeine, xanthene, gentisic acid andcylodextrins.

Examples of disintegrants include sodium starch gycolate, sodiumalginate, carboxymethyl cellulose sodium, methyl cellulose, andcroscarmellose sodium.

Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum, and tragacanth.

Examples of lubricants include magnesium stearate and calcium stearate.

Examples of pH modifiers include acids such as citric acid, acetic acid,ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoricacid, and the like; bases such as sodium acetate, potassium acetate,calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide,calcium hydroxide, aluminum hydroxide, and the like, and buffersgenerally comprising mixtures of acids and the salts of said acids. Atleast one function of inclusion of such pH modifiers is to control thedissolution rate of the drug, matrix polymer, or both, therebycontrolling the local drug concentration during dissolution. In somecases it has been determined that the MSSC values for some drugs arehigher when the solid amorphous drug dispersion dissolves relativelyslowly rather than fast, e.g., over 60 to 180 minutes rather than lessthan 60 minutes.

As was stated earlier, additives may be incorporated into the solidamorphous dispersion during or after its formation.

In addition to the above additives or excipients, use of anyconventional materials and procedures for formulation and preparation oforal dosage forms using the compositions of this invention known bythose skilled in the art are potentially useful.

Other features and embodiments of the invention will become apparent bythe following examples which are given for illustration of the inventionrather than limiting its intended scope. In the examples, reference ismade to a mini spray dryer (schematically illustrated in FIG. 1) and toa micro spray dryer, schematically illustrated in FIG. 2. These spraydryers were adapted from commercially available spray dryers sold byNIRO to downsize them to a size suitable for laboratory scale productionof spray dried drug products.

In the Examples, “mgA” is an acronym for “milligrams of active drug”,i.e., the non-salt free base or free acid if the compound is ionizable.“μgA” similarly means micrograms of active drug.

The mini spray-dryer shown in FIG. 1 consists of an atomizer in the topcap of a vertically oriented stainless steel pipe shown generally as 10.The atomizer is a two-fluid nozzle (Spraying Systems Co. 1650 fluid capand 64 air cap) where the atomizing gas is nitrogen delivered throughline 12 to the nozzle at 100° C. and a flow of 15 gm/min, and a testsolution to be spray dried is delivered through line 14 to the nozzle atroom temperature and a flow rate of 1.0 gram/min using a syringe pump(Harvard Apparatus, Syringe Infusion Pump 22, not shown). Filter paper16 with a supporting screen (not shown) is clamped to the bottom end ofthe pipe to collect the solid spray-dried material and allow thenitrogen and evaporated solvent to escape.

The micro spray dryer shown in FIG. 2 consists of an atomizer 102 in thetop of a vacuum flask 100 kept at 40° C. by a water bath 104. Atomizer102 is a two-fluid spray nozzle (NIRO Aeromatic, 2.7 mm ID air cap, 1.0mm ID fluid cap) where the atomizing gas is nitrogen delivered to thenozzle at ambient temperature and at 20 psi, and the drug/polymer testsolution 106 is delivered to nozzle 102 at 40° C. at a flow rate of 1.0gm/min using a peristaltic pump 108 (Masterflex, model 7553-60, withpump head #7013-20, and Norprene tubing #6404-13). Microporous celluloseextraction thimble 110 (Whatman Filter Co.) is mounted in a vacuum trap114 to collect the solid spray-dried material, and a vacuum of 400 mbar(monitored by vacuum gauge 112) is pulled on the system by means ofvacuum pump 116, which aids in solvent evaporation.

Example 1

A solution of compound and polymer was made by dissolving 133.0 mg of[R—(R*,S*)]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1-H-indole-2-carboxamide(Compound 1, shown below) and 67.0 mg of HPMCAS-MF (Shin Etsu,containing 23.4% methoxyl, 7.2% hydroxypropyl. 9.4% acetyl, 11.0%succinoyl, MW=8.0*10⁴, Mn=4.4*10⁴) in 10 gm of HPLC grade acetone(Burdick & Jackson). The compound/polymer solution was then placed in a20 mL syringe that was then inserted into a syringe pump.

Solvent was rapidly removed from the above solution by spraying it intothe mini spray-drying apparatus shown in FIG. 1, referred to herein asthe “mini” spray dryer. The resulting material was a dry, white,substantially amorphous powder.

Example 2

This example discloses an in vitro dissolution test termed the“syringe/filter” method. In this method the concentration of testcompound in solution is determined as a function of time. Test solutionis held in a syringe from which samples are expelled through a filter atpre-determined time points. In between expelling samples from thesyringe, the syringe is rotated (50 rpm) on a wheel held in an oven at37° C.

7.5 mg of the material of Example 1 was placed in an empty disposable 10mL syringe (Aldrich, Fortuna). A 20 GA hypodermic needle was attached tothe syringe, and 10 mL of a model-fasted duodenal (MFD) solution at 37°C. was drawn into the syringe. The MFD solution was composed ofphosphate-buffered saline solution (82 mM NaCl, 20 mM Na₂HPO₄, 47 mMKH₂PO₄, pH 6.5, 290 mOsm/kg) containing 14.7 mM sodium taurocholate(Fluka) and 2.8 mM 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine(Avanti Polar Lipids).

The MFD solution was prepared using the following procedure. Into a 100mL round bottom flask was weighed 0.788 gm of the sodium taurocholicacid, which was then dissolved in 5.0 mL of ambient HPLC methanol(Burdick & Jackson). To this solution was added 15.624 gm of the1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine in chloroform, suppliedby Avanti Polar Lipids as a 20 mg/mL solution. This mixture was thenmixed thoroughly by vortex mixer (Fisher Vortex Genie), and the solventremoved rapidly by roto-evaporator (Rotavapor RE121, Büchi), leaving adry white surface dispersion coating the flask. The surface dispersionwas then reconstituted with 200 mL of the 37° C. phosphate bufferedsaline.

The needle was then replaced with a 13 mm, 0.45 μm polyvinylidinediflouride syringe filter (Scientific Resources, Titan), and the syringewas vigorously shaken for 30 sec. After 30 sec, 6 drops of the solutionwas expelled and a subsequent 13 drop sample was delivered to a testtube. After expelling the sample, the syringe plunger was drawn back topull an air bubble into the syringe to aid in subsequent mixing and thesyringe placed back on a rotating wheel in a 37° C. oven. The sample wasdiluted 1:1 with a solution containing 60/40-1.7 wt % ammonium ascorbatein acetonitrile, and the concentration of compound analyzed on an HPLC(Hewlett Packard 1090 HPLC, Phenomenex Ultracarb ODS 20 analyticalcolumn, absorbance measured at 215 nm with a diode arrayspectrophotometer). The remaining solution in the syringe was mixed byrotating on a wheel at 50 rpm in a 37° C. temperature-controlled box.

Samples were taken after 5, 30, 60 and 180 minutes as described above,analyzed, and compound concentrations calculated. The concentration ofcompound in the filtrate as a function of elapsed time (time=0 when thesolid material of Example 1 is first mixed with aqueous solution) wasfound to be 17 μgA/ml at 5 min., 70 μgA/ml at 10 min., 120 μgA/ml at 30min., 127 μgA/ml at 60 min and 135 μgA/ml at 180 min., and 38 μgA/ml at1200 min. (see Table I, Example 9). This result showed that theHPMCAS/Compound 1 solid amorphous dispersion rapidly yields a highconcentration of dissolved compound (at least 12-fold higher than itsequilibrium solubility of 9 μgA/ml) in the dissolution medium and thissupersaturated concentration was maintained for at least 180 minutes.When crystalline compound was triturated and subjected to the samedissolution test, a maximum concentration of Compound 1 of 10 μA/ml wasobtained (See Comparative Example 1). Throughout the examples,triturated material indicates that the material was ground lightly byhand for 60 seconds using a mortar and pestle.

Example 3

This example discloses an in vitro dissolution test termed the“centrifuge” method. This method was used to test the dissolution ofmaterial made by essentially the same method as that described inExample 1 except that the concentration of Compound 1 was decreased by afactor of 2 to 66.5 mg such that the ratio of compound to polymer was1:1. (see Example 7, Table I).

In a 37° C. controlled temperature box, 1.8 mg of solid product fromExample 1 was accurately weighed into an empty microcentrifuge tube(polypropylene, Sorenson Bioscience Inc.). The theoretical maximumconcentration of compound in solution (e.g., if all compound dissolved)was 383 μgA/ml [1.8 mg dispersion (1000 μg/1 mg) (0.5 μg compound/μgdispersion) (0.764 compound assay)/1.8 ml=393 μgA/ml]. This value istermed the theoretical maximum supersaturated concentration and isabbreviated Theoretical MSSC. 1.8 mL of a 37 C phosphate buffered salinesolution (8.2 mM NaCl, 1.1 mM Na2HPO4, 4.7 mM KH2PO4, pH 6.5, 290mOsm/kg) containing 14.7 mM sodium taurocholic acid (Fluka) and 2.8 mM1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids)was added to the tube. The centrifuge tube was closed and a timer wasstarted. The tube was then mixed continuously at the highest speed on avortex mixer (Fisher Vortex Genie 2) for 60 seconds. The tube wastransferred to a centrifuge (Marathon, Model Micro A) allowed to standundisturbed for six minutes, then centrifuged at 13,000 G for 60seconds. A 25 uL sample was removed from the solids-free supernatant inthe centrifuge tube via pipette (Gilson Pipetman P-100) ten minutesafter the timer was started. Solids in the centrifuge tube wereresuspended by mixing the sample continuously on the vortex mixer for 30seconds. The centrifuge tube was returned to the centrifuge and allowedto stand undisturbed until the next sample was taken. Each sample wascentrifuged, sampled and resuspended as described previously. Eachsample was diluted 1:1 with a solution containing 60/40 1.7 wt %ammonium ascorbate/acetonitrile, and the concentration of compound wasdetermined by HPLC (Hewlett Packard 1090 HPLC, Phenomenex Ultracarb ODS20 analytical column, absorbance measured at 215 nm with a diode arrayspectrophotometer). Samples were taken after 10, 30, 60, 180, and 1,200minutes as described above, analyzed and compound concentrations werecalculated. The concentration of compound in the supernatant solutionfor the times listed above were 96, 121, 118, 125, and 40 μgA/ml,respectively. The composition and performance data is summarized inTable I as Example 7. The maximum compound concentration observed, 125μgA/ml, is termed the maximum supersaturated concentration of compoundand is abbreviated MSSC.

TABLE I EXAMPLE Drug Polymer Dg:Poly Analytical Theor. MSSC MSSC C₉₀C₁₂₀₀ C₁₈₀ NO. No. Type Ratio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL)(μgA/mL) (μgA/mL) 5 1 HPMCAS-MF 1:1 MINI syringe/filter 500 120 117 14120 6 1 HPMCAS-HF 1:1 MINI syringe/filter 500 82 80 20 82 7 1 HPMCAS-MF1:1 MICRO centrifuge 383 125 118 40 125 8 1 HPMCAS-MF 1:1 MICROsyringe/filter 500 120 116 100 120 9 1 HPMCAS-MF   1:0.5 MINIsyringe/filter 500 135 130 38 135 10 1 HPMCAS-MF 1:1 MICROsyringe/filter 500 117 115 36 115 11 1 HPMCAS-MF 1:2 MICROsyringe/filter 500 112 110 39 100 12 1 HPMCAS-MF 1:5 MICROsyringe/filter 500 108 96 96 95 13 1 HPMCAS-MF 1:9 MICRO syringe/filter89 86 82 85 83 14 1 HPMCAS-MF 1:9 MINI syringe/filter 545 520 333 520399

Example 4

A solution of compound and polymer was made by dissolving 200.0 mg of[R—(R*,S*)]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1-H-indole-2-carboxamide(Compound 1) and 1.8 gm of HPMCAS-MF (Shin Etsu, containing 23.4%methoxyl, 7.2% hydroxypropyl, 9.4% acetyl, 11.0% succinoyl, MW=8.0*10⁻⁴,Mn=4.4*10⁻) in 118 gm of HPLC grade acetone (Burdich & Jackson). Thecompound/polymer solution was then spray-dried.

Solvent was rapidly removed from the above solution by spraying it intothe spray-drying apparatus shown in FIG. 2, the “micro” spray dryer. Theresulting material was a dry, white, substantially amorphous powder.

Examples 5 to 14

Spray-dried dispersions of Compound 1 exemplifying the invention weremade as described in Example 1 (Mini Spray-dryer) or Example 4 (MicroSpray-dryer) except as noted in Table I. The dispersions were tested bythe method described in Example 2 or Example 3 as noted in Table I andthe results are tabulated in Table I.

Comparative Examples C1 to C4

The following tests of Compound 1 were conducted to aid in demonstratingthe superior solubilities of dispersions according to the inventionrelative to conventional forms of Compound 1. Dissolution tests wereconducted using the syringe/filter test described in Example 2 with fourmaterials: 1) triturated crystalline compound alone (Example C1), 2) asolid spray-dried dispersion of Compound 1 and PVAP (Example C2), 3) asolid spray-dried dispersion of Compound 1 and HPMCP (Example C3), and4) a solid spray-dried dispersion of Compound 1 and PVP (Example C4).The composition of each material and the results of the dissolutiontests are listed in Table II and should be compared to Examples 5 to 14in Table I. All HPMCAS dispersions showed much higher concentrations ofdissolved compound (80 to 520 μgA/ml) than the crystalline compoundalone (10 μgA/ml) and the compound concentration even after 1200 minuteswas 20 to 520 μgA/ml, at least twice the equilibrium solubility (i.e. 8to 10 μgA/ml). In addition it can be seen that although dispersionscomposed of matrix polymers other than HPMCAS (PVAP, HPMCP, PVP) showsupersaturation, this super saturation is not maintained as well as withHPMCAS (C₁₂₀₀ values are approximately equal to equilibrium solubility(9 to 13 μgA/ml) while C₁₂₀₀ values for HPMCAS dispersions are generally40 to 520 μgA/ml.

TABLE II Comparative Examples for Compound No. 1 Cpd Dissolution Theor.Example Cpd Polymer Polymer Test MSSC MSSC C90 C1200 C180 No. No. TypeRatio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) C1 1NONE 1:0 TRITURATED syringe/filter 98 10 10 9 8.5 C2 1 PVAP 1:1 MINIsyringe/filter 500 104 82 9 17 C3 1 HPMCP 1:1 MINI syringe/filter 500127 123 13 106 C4 1 PVP 1:1 MINI syring/filter 500 133 125 13 114

Example 15

In this example, a solid amorphous dispersion of Compound 1 was preparedusing a relatively large spray dryer that produces dispersions at a rateof about 0.5 to 1.0 g/min. A compound/polymer solution was made bydissolving 6 g of Compound 1 and 3 g HPMCAS-MF in 600 g of acetone. Thecompound/polymer solution was then placed in a pressure vessel thatdelivers the compound/polymer solution at a controlled rate to acommercial spray dryer. (Mobile Minor Hi-Tec for Non-Aqueous Feed SprayDryer, manufactured by NIRO A/S, Soburg, Denmark)

The Niro spray dryer consists of an atomizer that fits into the top of adrying chamber. The atomizer is a 2-fluid nozzle. The atomizing gas wasnitrogen delivered to the nozzle at and a flow of 180 g/min. TheCompound/polymer solution described above was delivered to the nozzle atroom temperature at a rate of 45 g/min. Drying gas was delivered to thedrying chamber through an inlet duct that surrounds the 2-fluid nozzle.The drying gas was nitrogen heated to 120° C. and delivered to thedrying chamber at 1500 s/min. The spray-dried material exited thechamber with the drying gas through transport ducts and into a cyclone.At the top of the cyclone is an exhaust vent that allows the nitrogenand evaporated solvent to escape. The spray-dried material was collectedin a canister. The material was a dry, white, substantially amorphouspowder.

This dispersion was tested by using the method described in Example 2.Sufficient dispersion was used in this test such that the theoreticalmaximum concentration of Compound 1 (if it all dissolved) was 500μgA/ml. The maximum concentration of Compound 1 observed was 137 μgA/ml.Ninety minutes after the start of this test, the concentration ofCompound 1 was 130 μgA/ml and at 1200 minutes the concentration was 22μgA/ml. Comparison of these results to those for Example 9 in Table Ishow that the dispersion made on the large spray dryer performedsimilarly to that made on the “mini” spray dryer.

Examples 16 to 18

Spray-dried dispersions of Compound 2,3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine,structure shown below, exemplifying the invention were made as describedin Example 1 (Mini Spray-dryer), except as noted in Table III. Thedispersions were tested by the method described in Example 3 and notedin Table III and the results are tabulated in Table III.

TABLE III EXAMPLE Drug Polymer Dg:Poly Analytical Theor. MSSC MSSC C₉₀C₁₂₀₀ C₁₈₀ NO. No. Type Ratio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL)(μgA/mL) (μgA/mL) 16 2 HPMCAS-HF 1:9 MIN centrifuge 95 73 69 46 — 17 2HPMCAS-MF 1:9 MIN centrifuge 105 103 92 63 — 18 2 HPMCAS-MF 1:2 MINcentrifuge 100 66 54 51 —

Comparative Examples C5 and C6

The following tests of Compound 2 in crystalline form either alone orsimply triturated by hand (as described in Example 2) with HPMCAS arefor comparison to Examples 16 to 18 in Table III. The composition of thematerials and the results of dissolution tests are shown in Table IV.Much higher compound concentrations were achieved with the HPMCASdispersions relative to crystalline compound either alone or mixed (butnot dispersed) in HPMCAS. This demonstrates that the compound should bedispersed in amorphous form in the HPMCAS according to this inventioninstead of triturating the crystalline compound with HPMCAS to achievehigh levels of supersaturation that are maintained for long timeperiods.

TABLE IV Comparative Examples for Compound No. 2 Cpd Dissolution Ex CpdPolymer Polymer Test Theor. MSSC MSSC C90 C1200 C180 No. No. Type RatioSprayer Method (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) C5 2 NONE1:0 TRITURATED centrifuge 100 18 18 13 — C6 2 HPMCAS- 1:9 TRITURATEDcentrifuge 85 12 12 — — HF

Examples 19 to 22

Spray-dried dispersions of Compound3,5-(2-(4-(3-benzisothiazolyl)-piperazinyl)ethyl-6-chlorooxindole(ziprasidone), shown below, exemplifying the invention were made asdescribed in Example 1 (Mini Spray-dryer) except as noted in Table V.The dispersions were tested by the method described in Example 3 asnoted in Table V and the results are tabulated in Table V.

TABLE V EXAMPLE Drug Polymer Dg:Poly* Analytical Theor. MSSC MSSC C₉₀C₁₂₀₀ C₁₈₀ NO. No. Type Ratio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL)(μgA/mL) (μgA/mL) 19 3 HPMCAS-HF 1:9 MN centrifuge 189 98 59 — — 20 3HPMCAS-HF 1:5 MN centrifuge 162 101 40 11 — 21 3 HPMCAS-MF 1:9 MNcentrifuge 176 138 7  4 — 22 3 HPMCAS-LF 1:9 MN centrifuge 151 105 12 —— *Drug:Polymer ratio is based on total weight of hydrochloride salt.

Comparative Examples C7 and C8

The following tests of Compound 3 in crystalline form alone andtriturated with HPMCAS are for comparison to Examples 19 to 22 in TableV. The composition of the materials and the results of dissolution testsare shown in Table VI. The HPMCAS dispersions yielded much highercompound concentrations than either the crystalline compound alone orthe crystalline compound triturated by hand with HPMCAS showing theexcellent performance of the composition of the invention and theimportance of dispersing the compound in HPMCAS in an amorphous form.The results shown in Table V also demonstrate that for dispersions ofCompound 3, HPMCAS-HF maintains a higher compound concentration (compareC₉₀ values), compared to HPMCAS-MF and HPMCAS-LF.

TABLE VI Comparative Examples for Compound No. 3 Cpd Dissolution Theor.Ex Cpd Polymer Polymer Test MSSC MSSC C90 C1200 C180 No. No. Type RatioSprayer Method (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) C7 3 NONE1:0 TRITURATED Centrifuge 180 27 4 1 — C8 3 HPMCAS- 1:5 TRITURATEDCentrifuge 176 37 29 4 — HF

Example 23

A dispersion of Compound 3 was made by dissolving 10 g of Compound 3 and90 g of HPMCAS-HF in 2400 g methanol. This compound/polymer solution wasspray-dried using the Niro spray dryer as described in Example 15. Thecompound/polymer solution was delivered to the 2-fluid nozzle at roomtemperature at a flow rate of 25 g/min. All other conditions were thesame as those described in Example 15.

This dispersion was tested using the method described in Example 3 (the“centrifuge” method). Sufficient dispersion was tested such that theconcentration of Compound 3 would be 200 μgA/ml if all of the compounddissolved. The maximum compound concentration observed (C_(max)) was 107μgA/ml. The compound concentration after 90 minutes and 1200 minutes was60 μgA/mland 32 μgA/ml, respectively.

Example 24

A comparison of the performance of dispersions of the present invention(spray dried) with those prepared conventionally by slow evaporation ofsolvent was made as follows. A dispersion of the present invention(Example 24) was prepared from 500 grams of compound/polymer solutioncomprising 0.2 wt % Compound 3 and 1.8 wt % HPMCAS-HF in methanol(USP/NF grade) using the Niro spray dryer and procedure described inExample 23. 5.8 grams of spray-dried dispersion was recovered.

Comparative Examples C9 and C10

A conventional dispersion (Example C9) was prepared as follows. 100grams of compound/polymer solution of the same composition as that usedin Example 24 was placed in a 500 ml round-bottom flask. Solvent wasremoved from the solution at reduced pressure at 40° C. using a rotaryevaporator. After 30 minutes, the material appeared to be dry and it wasscraped from the flask. The conventional dispersion was placed undervacuum for several hours to remove any traces of solvent. 1.8 grams ofconventional dispersion was recovered.

The two dispersions described above (Example 24 and Example C9) andcrystalline compound (Comparative Example C10) were tested using thecentrifuge method described in Example 3. The results of this test arelisted in Table VII. The dispersion prepared by spray drying performedmuch better than dispersion prepared by conventional rotary evaporation.

TABLE VII Cpd Dissolution Theor. Ex Cpd Polymer Polymer Drying Test MSSCC3 C10 C20 C40 No. No. Type Ratio Equipment Method (μgA/mL) (μgA/mL)(μgA/mL) (μgA/mL) (μgA/mL) 24 3 HPMCAS- 1:9 Niro centrifuge 195 128 9875 47 HF Spray Dryer C9 3 HPMCAS- 1:9 rotary centrifuge 204 0 0 0 3.9 HFevaporator C10 3 NONE 1:0 — centrifuge 180 27 22 19 7

Examples 25 to 27

Spray-dried dispersions of Compound 4, Griseofulvin,7-chloro-4,6-dimethoxy-courmaran-3-one-2-spiro-1′-(2′-methoxy-6′-methylcyclohex-2′en-4′-one),shown below, exemplifying the invention were made as described inExample 4 (Micro Spray-dryer) except as noted in Table VIII. Thedispersions were tested by the method described in Example 2 as noted inTable VIII and the results are tabulated in Table VIII.

TABLE VIII EXAMPLE Drug Polymer Dg:Poly Analytical Theor. MSSC MSSC C₉₀C₁₂₀₀ C₁₈₀ NO. No. Type Ratio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL)(μgA/mL) (μgA/mL) 25 4 HPMCAS-MF 1:9 MCRO syringe/filter 200 185 175 125175 26 4 HPMCAS-MF 1:4 MCRO syringe/filter 200 175 165 — 160

Comparative Example C11

This example shows the results of a dissolution test of Compound 4 inits crystalline form in Table IX for comparison with Examples 25 to 27,Table VIII. Much higher compound concentrations are achieved with theHPMCAS dispersions than with crystalline compound alone.

TABLE IX Comparative Examples for Compound No. 4 Dissolution Theor.Example Cpd Polymer Cpd:Polymer Test MSSC MSSC C60 C90 C180 No. No. TypeRatio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) C11 4NONE 1:0 TRITURATED syringe/filter 200 18 17 15 —

Example 28

A spray-dried dispersion of Compound 5, nifedipine,1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylic aciddimethyl ester, structure shown below, exemplifying the invention wasmade as described in Example 4 (Micro Spray-dryer) except as noted inTable X. The dispersion was tested by the method described in Example 2as noted in Table X and the results are tabulated in Table X.

TABLE X EXAMPLE Drug Polymer Dg:Poly Analytical Theor. MSSC MSSC C₉₀C₁₂₀₀ C₁₈₀ NO. No. Type Ratio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL)(μgA/mL) (μgA/mL) 28 5 HPMCAS-MF 1:9 MCRO syringe/filter 100 105 90 8895

Comparative Example C12

This example shows the results of a dissolution test of Compound 5 inits crystalline form in Table XI for comparison with Example 28. A muchhigher compound concentration is achieved and sustained for 1200 minuteswith the HPMCAS dispersion relative to crystalline compound alone.

TABLE XI Comparative Examples for Compound No. 5 Dissolution Theor.Example Cpd Cpd:Polyme Test MSSC MSSC C90 C1200 C180 No. No. PolymerRatio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) C12 5NONE 1:0 TRITURATED syringe/filter 100 19 18 19 19

Example 29 and Comparative Examples C13 and C14

A comparison of the performance of a dispersion of Compound6,5,5-diphenylhydantoin (phenyloin), shown below, and HPMCAS of thepresent invention (spray-dried) with those prepared conventionally byslow evaporation of solvent was made as follows. A dispersion of thepresent invention (Example 29) was prepared from 720 grams of acompound/polymer solution prepared by dissolving 0.10 wt % of Compound 6(Aldrich) and 0.90 wt % HPMCAS-MF (Shin-Etsu) in acetone (HPLC grade).This compound/polymer solution was spray-dried using the Nirospray-dryer and procedure described in Example 23. 6.8 grams ofspray-dried dispersion was recovered.

A conventional dispersion (Example C13) was prepared from 90 grams of acompound/polymer solution of the same composition as that used inExample 29 using the procedure described for Comparative Example C9except that the solvent was evaporated at 30° C. After 30 minutes, thematerial coated the surface of the flask as a solid cake and it wasscraped from the flask. 0.9 grams of product was recovered.

The two dispersions described above (Example 29 and Comparative ExampleC13) and crystalline compound (Comparative Example C14) were testedusing the centrifuge method described in Example 3. The results of thistest are listed in Table XII.

The results clearly show that over the first 40 minutes of dissolutionthat the dispersions of the present invention achieve significantlyhigher compound concentrations than either crystalline compound(Comparative Example C14) or the conventional dispersion (ComparativeExample C13).

TABLE XII Comparative Examples for Compound No. 6 Dissolution Theor.Example Cpd:Polymer Test MSSC C3 C10 C20 C40 C90 No. Cpd No. PolymerRatio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL) (μgA/mL)(μgA/mL) 29 6 HPMCAS- 1:9 Niro centrifuge 96 97 96 90 97 99 MF C13 6HPMCAS- 1:9 rotary centrifuge 103 23 43 58 78 90 MF evaporator C14 6NONE 1:0 centrifuge 100 14 20 28 34 50

Example 30 and Comparative Example C15

A spray-dried dispersion of Compound 7,(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea,structure shown below, exemplifying the invention was made as describedin Example 1 (Mini Spray-dryer) except as noted in Table XIII. Thedispersion, along with crystalline Compound 7 (Comparative Example C15),were tested by the method described in Example 3 as noted in Table XIIIand the results are tabulated in Table XIII. The observed concentrationof Compound 7 was much higher for the dispersion relative to thecrystalline compound.

TABLE XIII EXAMPLE Drug Polymer Dg:Poly Analytical Theor. MSSC MSSC C₉₀C₁₂₀₀ C₁₈₀ NO. No. Type Ratio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL)(μgA/mL) (μgA/mL) 30 7 HPMCAS-HF 1:9 MINI centrifuge 1045 550 320 220 —

Example 31 and Comparative Example C16

A spray-dried dispersion of Compound 8,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine,shown below, exemplifying the invention was made as described in Example1 (Mini Spray-dryer) except as noted in Table XIV. The dispersion, alongwith crystalline Compound 8 (Comparative Example C16), were tested bythe method described in Example 3 and noted in Table XIV and the resultsare tabulated in Table XIV. The observed concentration of Compound 8 wasmuch higher for the dispersion relative to the crystalline compound.

TABLE XIV EXAMPLE Drug Polymer Dg:Poly Analytical Theor. MSSC MSSC C₉₀C₁₂₀₀ C₁₈₀ NO. No. Type Ratio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL)(μgA/mL) (μgA/mL) 31 8 HPMCAS-LF 1:2 MINI centrifuge 477 467 405 167 —C16 8 None 1:0 — centrifuge 500 22 22 22 —

Example 32 and Comparative Example C17

A spray-dried dispersion of Compound 9, 1H-Indole-2-caboxamide,5-chloro-N-[3-(3,4-dihydroxy-1-pyrrolidinyl)-2-hydroxy-3-oxo-1-(phenylmethnyl)propyl]-,[R—[R*, S*-(cis)]]-, exemplifying the invention was made as described inExample 1 (Mini Spray-dryer) except as noted in Table XV. Thedispersion, along with crystalline Compound 9 (Comparative Example C17),were tested by the method described in Example 3 as noted in Table XVand the results are tabulated in Table XV. The observed concentration ofCompound 9 was much higher for the dispersion relative to thecrystalline compound.

TABLE XV EXAMPLE Drug Polymer Dg:Poly Analytical Theor. MSSC MSSC C₉₀C₁₂₀₀ NO. No. Type Ratio Sprayer Method (μgA/mL) (μgA/mL) (μgA/mL)(μgA/mL) 32 9 HPMCAS-MF 1:1 MN centrifuge 515 515 475 515 C17 9 None 1:0— centrifuge 500 194 158 194

Example 33

This example demonstrates that spray-dried dispersions of Compound 1 andHPMCAS, when orally dosed to beagle dogs, give a higher systemiccompound exposure (Cmax and AUC) than observed after dosing an aqueoussuspension of crystalline Compound 1. The following formulations wereorally dosed:

Formulation A: Aqueous suspension of crystalline Compound 1 in 0.5%methylcellulose. Dosed 5 mgA/kg at 2 ml/kg.Formulation B Solution of Compound 1 at 10 mgA/mlinpolyethyleneglycol-400 (PEG-400). Dosed 10 mg/kg at 1 ml/kg.

Formulation C:

Aqueous suspension of a 1:1 (w/w) Compound 1/HPMCAS spray-drieddispersion at 2.5 mgA/mlin 2% polysorbate-80. Dosed at 3.7 mgA/kg at 2ml/kg.

Formulation D:

Capsule (size#2) containing 53.1 mgA Compound 1 as a 1:1 (w/w) Compound1/HPMCAS spray-dried dispersion. The capsule fill composition ispresented in Table XVI.

Formulation E

Capsule (size #0) containing 200 mgA Compound 1 as a 2:1 (w/w) Compound1/HPMCAS spray-dried dispersion. The capsule fill composition ispresented in Table XVI.

Formulation F

Capsule (size#0) containing 200 mgA Compound 1 as a 2:1 (w/w)Compound1/HPMCAS spray-dried dispersion. The capsule fill composition ispresented in Table XVI.

Dogs were dosed either after an overnight fast, or after a meal composedof 14 g dry dog food, 8 g olive oil, and 50 ml water. Blood (3 ml) wascollected from the jugular vein pre-dosing and at 0.17, 0.5, 1, 2, 4, 7,10, 24, 32, and 48 hour post-dosing.

To 100 μl of a plasma sample, 5 ml methyl-tert-butyl ether (MTBE) and 1ml 500 mM sodium carbonate buffer (pH9) were added, and the sample wasvortexed for 1 min, then centrifuged for 5 min. The aqueous portion ofthe sample was frozen in a dry ice/acetone bath and the MTBE layer wasdecanted and evaporated in a vortex evaporator at 55° C. The sample wasreconstituted with 75 μl of a mobile phase composed of 45% acetonitrile,55% 50 mM NaH2PO4/30 mM triethylamine (pH 3). Analysis was carried outby HPLC, using a Waters Nova-Pak C-18 column (3.9 mm×150 mm), with aC18/5 u guard column, at a temperature of 26° C., at a flow rate of 1ml/min. Detection was by fluorescence (excitation wavelength 290 nm;emission wavelength 348 nm).

Pharmacokinetic data are presented in Table XVII. C_(max) is the maximumobserved plasma Compound1 concentration, averaged over the number ofdogs dosed with each formulation. AUC o-∞ is the average area under theplasma Compound 1 concentration vs. time curve.

These data demonstrate that spray-dried Compound1/HPMCAS dispersions,when orally dosed to beagle dogs, give a higher systemic Compound 1exposure than after dosing an aqueous suspension of crystalline Compound1.

TABLE XVI Component Formulation D Formulation E Formulation F Compound44%  — — 1/HPMCAS (1:1, w/w) Compound — 60%  50%  1/HPMCAS (2:1, w/w)Lactose, fast flow 22%  15%  10.8%   Microcrystalline 18.8%   15% 32.2%   Cellulose¹ Sodium Starch 8% 7% 5% Glycolate² Sodium laurylSulfate 2% 2% 1% Magnesium Stearate 1% 1% 1% ¹Avicel-102 ® ²Explotab ®

TABLE XVII Canine pharmacokinetics after oral dosing of Compound 1formulations. Canines were in fasted state, except where indicated. CmaxAUC o-∞ % Formulation Dose¹ n² (uM) (uM × hr/ml) Bioavailability³ A   5mgA/kg 2 0.3 1.3 2.0 B   10 mgA/kg 4 11.8 92.9 72.5 C  3.7 mgA/kg 4 4.917.1 35.0 D 53.1 mgA 3 3.3 15.8 31.0 E  200 mgA 4 9.1 76.3 33.4 F  200mg A 4 9.0 82.4 45.6 E (fed)  200 mg A 4 7.6 182.5 109.5 ¹For comparisonpurposes, the average weight of beagle dogs used in this study wasaround 10 kg. ²Number of dogs studied ³Relative to a 10 mgA/kgintravenous dose given to a separate group of dogs.

Example 34

This example demonstrates that dosing a spray dried dispersion ofziprasidone/HPMCAS to dogs results in a higher systemic ziprasidoneexposure than observed after dosing crystalline ziprasidone. Systemicexposure was measured as the area under the plasma ziprasidoneconcentration vs. time curve (AUC).

On two occasions, after an overnight fast, five beagle dogs were dosedwith 20 mgA ziprasidone in either (a) a capsule containing a spray-dried9:1 HPMCAS-MF/Ziprasidone dispersion, or (b) a capsule containing apowder formulation of crystalline ziprasidone (30.2% ziprasidonehydrochloride, 58.6% hydrous lactose, 10% pregelatinized starch, 1.25%MgStearate). Following administration of the capsule, dogs were gavagedwith 50 ml water. Water and food were witheld until 8 hr after dosing.

Pre-dosing, and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hr post-dosing, bloodsamples were taken, and plasma was harvested. Ziprasidone concentrationwas assayed using an HPLC assay. The mobile phase consisted of 40/60aqueous NaH2PO4 (0.005M)/acetonitrile, and the column was a CN-Chromegacolumn, 5 u, CN+NP, 25 cm×4.6 mm (ES Industries). The flow rate was 1.5ml/min, and detection was at 315 nm.

For the capsule containing crystalline ziprasidone, the observed averageAUC(O-inf) was 561.6 ng×hr/ml. For the capsule containing theZiprasidone/HPMCAS dispersion, the average AUC was 1056 ng×hr/ml.

1. A process for making a solid dispersion consisting of a sparinglywater-soluble drug, hydroxypropyl methyl cellulose acetate succinate(HPMCAS), and a surface-active agent, said drug being molecularlydispersed and amorphous in said dispersion, said process consistingessentially of the steps of: (a) providing a solution consisting of asparingly water-soluble drug, HPMCAS, a surface-active agent, and asolvent or a solvent and water mixture, said solvent being a compound inwhich said drug, said surface-active agent, and HPMCAS are mutuallysoluble, said solution having a ratio of said drug to HPMCAS of from 1to 0.4 to 1 to 20; (b) breaking up said solution into small droplets,wherein said droplets range in size from 1 to 500 μm; (c) directing saiddroplets and a drying gas into a drying chamber to cause evaporation ofa sufficient amount of said solvent from said droplets to causesolidification of said droplets in less than 5 seconds to form saidsolid dispersion.
 2. The process of claim 1, wherein said surface-activeagent is selected from fatty acid and alkyl sulfonates, benzethaniumchloride, docusate sodium, polyoxyethylene sorbitan fatty acid esters,sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, and lecithin.
 3. Theprocess of claim 1, wherein said surface-active agent comprises up to 25wt % of said solid dispersion.
 4. A process for making a soliddispersion consisting of a sparingly water-soluble drug andhydroxypropyl methyl cellulose acetate succinate (HPMCAS), said drugbeing molecularly dispersed and amorphous in said dispersion, saidprocess consisting essentially of the steps of: (a) providing a solutionconsisting of a sparingly water-soluble drug, HPMCAS, and a solvent or asolvent and water mixture, said solvent being a compound in which saiddrug and said HPMCAS are mutually soluble, said solution having a ratioof said drug to HPMCAS of from 1 to 0.4 to 1 to 20; (b) breaking up saidsolution into small droplets, wherein said droplets range in size from 1to 500 μm; (c) directing said droplets and a drying gas into a dryingchamber to cause evaporation of a sufficient amount of said solvent fromsaid droplets to cause solidification of said droplets in less than 5seconds to form particles of said solid dispersion.
 5. The process ofclaim 1 or 4, wherein said solvent is a mixture of compounds.
 6. Theprocess of claim 5 wherein said solvent is selected from one or more ofmethanol, ethanol, n-propanol, iso-propanol, butanol, acetone, methylethyl ketone, methyl iso-butyl ketone, ethyl acetate, propylacetate,acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane,dimethylacetamide, dimethylsulfoxide, and water.
 7. The process of claim1 or 4, wherein said solvent has a boiling point of less than 150° C. 8.The process of claim 1 or 4, wherein HPMCAS is present in an amount insaid solution that constitutes at least 50 wt % of said soliddispersion.
 9. The process of claim 1 or 4, wherein said solidificationoccurs in less than 2 seconds.
 10. The process of claim 1 or 4, whereinsaid drying gas is heated.
 11. The process of claim 1 or 4, wherein theconcentration of drug in said solvent is less than 20 g/100 g of saidsolvent.
 12. A process for making a solid dispersion comprising asparingly water-soluble drug, hydroxypropyl methyl cellulose acetatesuccinate (HPMCAS), and a surface-active agent, said drug beingmolecularly dispersed and substantially completely amorphous in saiddispersion, said process consisting essentially of the steps of: (a)providing a solution comprising a sparingly water-soluble drug, HPMCAS,a surface-active agent, and a solvent, said solvent being a compound inwhich said drug, said surface-active agent, and HPMCAS are mutuallysoluble, said solution having a ratio of said drug to HPMCAS of from 1to 0.4 to 1 to 20; (b) breaking up said solution into small droplets,wherein said droplets range in size from 1 to 500 μm; (c) directing saiddroplets and a drying gas into a drying chamber to cause evaporation ofa sufficient amount of said solvent from said droplets to causesolidification of said droplets in less than 5 seconds to form saidsolid dispersion.